This application for a Career Development Award (K08) is designed to study how leptin affects B cell function. The applicant has generated preliminary data demonstrating a defective humoral response to NP immunization (both T-dependent and T-independent) in leptin deficient (ob/ob) or leptin receptor deficient (db/db) mice. Naive ob/ob and db/db mice display an abnormal distribution of B cell subsets and decreased levels of basal serum immunoglobulin (Ig) G when compared to wild type mice. In addition, ELISPOT analysis following immunization with NP-Ficoll (T-independent response) revealed increased numbers of NP-specific IgM, but not IgG B cells in ob/ob and db/db mice, in contrast with significantly lower levels of serum IgM or IgG anti-NP antibodies. These results demonstrate in mice which lack leptin signaling in vivo, more B cells become activated after NP-Ficoll immunization however they seem to have reduced secretion of antibodies or produce antibodies with lower affinities than wild type suggesting a defect in repertoire selection or perhaps in class switching. We propose three specific aims that will address the following assumptions: (1) we hypothesize that in the absence of leptin signaling, there is a defect in B cell function; (2) we propose that the defect in B cell function in the absence of leptin signaling is, at least in part, B cell intrinsic. This hypothesis is supported by our observation that an impaired humoral response to NP is transferable to RAG2-/- mice by adoptive transfer of ob/ob or db/db B cells; (3) we theorize that leptin signaling can cross talk with B cell receptor (BCR) signaling pathways. The training plan will allow the applicant to acquire new knowledge of methodological approaches to B cell biology and the proposal will broaden our understanding of the interplay between metabolic states and immunity. The training goals will be accomplished through the completion of the research plan and educational activities in the area of endocrine/metabolism physiology, experimental design, statistics and ethics. The training experiences in this award will provide the applicant with the necessary skills and experiences to independently undertake a career in investigative medicine and effectively compete for independent grant support in his current institution or elsewhere.